Abstract
Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Angiotensinogen / biosynthesis
-
Angiotensinogen / blood
-
Angiotensinogen / genetics
-
Angiotensinogen / metabolism*
-
Animals
-
Calcium-Binding Proteins
-
Cell Growth Processes / physiology
-
Ephrin-B2 / biosynthesis
-
Female
-
Humans
-
Intracellular Signaling Peptides and Proteins
-
Liver / metabolism
-
Liver / pathology
-
Liver Neoplasms, Experimental / blood supply*
-
Liver Neoplasms, Experimental / genetics
-
Liver Neoplasms, Experimental / metabolism
-
Liver Neoplasms, Experimental / pathology
-
Male
-
Membrane Proteins / biosynthesis
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Neovascularization, Pathologic / genetics
-
Neovascularization, Pathologic / metabolism
-
Neovascularization, Pathologic / pathology
-
Proto-Oncogene Proteins / biosynthesis
-
RNA, Messenger / biosynthesis
-
RNA, Messenger / genetics
-
Receptor, Notch4
-
Receptors, Notch / biosynthesis
Substances
-
Adaptor Proteins, Signal Transducing
-
Calcium-Binding Proteins
-
DLL4 protein, mouse
-
Ephrin-B2
-
Intracellular Signaling Peptides and Proteins
-
Membrane Proteins
-
Proto-Oncogene Proteins
-
RNA, Messenger
-
Receptor, Notch4
-
Receptors, Notch
-
Angiotensinogen
-
Notch4 protein, mouse